Tumor necrosis factor (TNF), especially TNF-α, is known to be released from inflammatory cells and thus cause a variety of cytotoxic, immune and inflammatory responses. It is known that TNF-α is involved in the development or prolongation of many inflammatory diseases and autoimmune diseases, and, when released into blood to act systemically, TNF-α causes severe septicemia and septicemic shock. As such, since TNF-α is a factor widely involved in the immune system of a living body, drugs for inhibiting TNF-α have been actively developed. TNF-α is biosynthesized in an inactive form and cleaved by a protease to become an active form, and an enzyme involved in this activation is referred to as a tumor necrosis factor-converting enzyme (TACE). Thus, substances for inhibiting the TACE may treat, alleviate, and prevent diseases, conditions, abnormal conditions, poor conditions, poor subjective symptoms, and the like that are caused by TNF-α (KR2011-0060940A).
Fibrosis is a disease that causes abnormal formation, accumulation, and deposition of extracellular matrices by fibroblasts, and refers to abnormal accumulation of collagen matrixes due to injury or inflammation that changes the structure and function of various tissues. Regardless of the onset location of fibrosis, most etiology of fibrosis includes excessive accumulation of collagen matrices replacing normal tissues. In particular, fibrosis occurring in the kidneys, the liver, the lungs, the heart, bones or bone marrow, and skin induces dysfunction of organs and eventually leads to death in severe cases. The fibroblasts serve to form an extracellular matrix precursor under a normal condition to form a fibrous tissue. The extracellular matrix, which is an intercellular substance of connective tissues, exists in the form of proteins such as fibronectin, laminin, chondronectin, and collagen.
Meanwhile, TGF-β plays a very diverse role in abnormal formation and accumulation of extracellular matrices by fibroblasts, cell proliferation, inflammatory responses, and cancer cell metastasis, and many cellular signaling pathways and targets have been identified. Thus, research into TGF-β has been conducted in many disease models, and research into and drug development of fibrotic diseases and cancer have been most actively conducted. TGF-β, which is a cell proliferation regulatory factor, has been reported to induce or restrict cell proliferation and thus play a vital role in the development of various diseases including cancer, heart diseases, and diabetes, and various physiological activities thereof have been reported. For example, there are actions such as the inhibition of TGF-β synthesis (the inhibition of the production of cell proliferation regulatory factors), TGF-β antagonist action (the disturbance of TGF receptors and signal transduction hindrance), platelet-derived growth factor (PDGF) antagonist action (the inhibition of angiogenesis inducing factors), p38 MAP kinase inhibitor action (the inhibition of cell proliferation signaling enzymes), anti-inflammation (the inhibition of TNF-alpha and MAPK production), and the like. Thus, if a novel pharmaceutical composition capable of more directly inhibiting TGF-β or blocking signal transduction pathways involved by TGF-β, and having no side effects can be developed, a variety of diseases caused by fibrosis and aging may be prevented and treated.
The wound healing process is largely divided into inflammation, granulation, epithelialization, and fibroplasia. In inflammation, necessary cells (fibroblasts, epithelial cells, etc.) are activated. Subsequently, in granulation, fibroblasts deposit collagen, and thus the amount of collagens increases and a wound becomes mature. In addition, changes in keratinocytes occur at the wound site, and the epidermis of the wound site becomes thick and gradually proceeds into a state in which epithelial cells transfer from basal cells below the epidermis to the epidermis, which is referred to as epithelialization. As fibroplasia proceeds through the epithelialization, collagen fibers form a collagenous matrix to fill the wound site, and this process continues to proceed for a long period of time and is terminated, thereby completing wound healing. Thus, the proliferation of epithelial cells and the production of collagen may also be considered as an important mechanism in wound healing and antiaging action.